These studies are designed to increase our understanding of the neurochemical mechanisms relevant to cocaine and opioid abuse, which is critical for the development of effective treatment strategies. Cocaine, morphine, and heroin are widely abused substances that activate dopamine- rich regions of the brain, and many studies suggest that there are interactions between the actions of psychomotor stimulants and opioids. The objective of this project is to examine what role opioid receptors play in the development of tolerance and sensitization to cocaine and the manner by which cocaine interacts with opioid receptors. Chronic continuous cocaine administration produces large increases in locomotor activity, to which rats become partially tolerant over several days. Continuous morphine administration produces moderate increases in locomotor activity which remain constant. When co-administered, they produce levels of activity greater than either drug alone, and the tolerance that is observed to cocaine is less pronounced. Studies examining the mechanism by which this effect occurs are currently underway. Chronic treatment with an opioid receptor antagonist produces an increase in the number of mu-opioid receptors in the brain. There are also increases in opioid receptor function following chronic antagonist administration, i.e. an increase in receptor regulation of second messenger function in vitro, and of opioid analgesia in vivo. These receptors are also increased in specific brain regions following chronic, continuous cocaine treatment. An opioid agonist such as morphine produces a down-regulation (decrease) of_mu-opioid receptors, and tolerance to opioid analgesia. When cocaine and morphine are chronically co-administered, there is a loss of tolerance normally associated with chronic morphine treatment. These findings, together with the in vitro receptor and functional assays, suggest that the effects of chronic cocaine on mu-opioid receptors are similar to those seen following opioid antagonist treatment. Since cocaine does not bind to opioid receptors, this effect is likely via an indirect action (eg. release of an agent that binds to opioid receptors or a heterologous regulation of receptors regulating common transduction systems). Treatment with a selective inhibitor of either dopamine, norepinephrine, or serotonin had no effect on opioid receptors, suggesting that cocaine may not exert its opioid altering effects through any individual system, but may require the combination of two, or all three systems. Further examination of the effects of these compounds on opioid receptor function are underway. These findings suggest that cocaine has a unique interaction with the opioid system. Thus, this system may serve as a target for the development of medical therapies for cocaine abuse which would result in a substantial betterment of the public health through a limitation on the spread of cocaine abuse and HIV infection.